The hormone irisin is necessary for the cognitive benefits of exercise in healthy mice and can rescue cognitive decline associated with Alzheimer’s disease, according to a study published August 20 in Nature Metabolism.

According to the authors, these results support the hypothesis that irisin undergirds the cognitive benefits of exercise—a link that has been long debated. In addition, this study has “paved the way for thinking whether irisin could be a therapeutic agent against Alzheimer’s disease,” says biologist Steffen Maak with the Leibniz Institute for Farm Animal Biology in Germany, who has been critical of the methods used to study irisin in the past and was not involved in the study.

Many studies have found that exercise is good for the brain, but the molecular mechanisms responsible for the cognitive boost have remained elusive. During her postdoctoral studies, neuroscientist Christiane Wrann found that the gene that codes for irisin becomes highly expressed in the brain during exercise—one of the first studies linking irisin with the brain.

See  “Irisin Skepticism Goes Way Back

When she joined the faculties at Massachusetts General Hospital and Harvard Medical School, she decided to investigate the hormone further. Wrann, who holds a patent related to irisin and is academic cofounder and consultant for Aevum Therapeutics, a company developing drugs that harness the protective molecular mechanisms of exercise to treat neurodegenerative and neuromuscular disorders, began to investigate whether irisin mediates the positive effects of exercise on the brain.

She and her group engineered mice that cannot produce irisin and put them through a series of learning tasks. After exercising irisin-deficient and wildtype mice on running wheels, the researchers tested their spatial learning and memory. While wildtype mice showed cognitive improvements after exercise as expected, the irisin-deficient mice did not. “This was the first really striking finding in the paper, and we then set out to find the mechanism,” Wrann recalls.

Next, the group tested irisin’s relationship with Alzheimer’s disease (AD) by breeding their irisin-deficient mice with AD model mice that overexpress mutated genes that cause them to develop amyloid plaques and cognitive deficits at 6 months of age. In cognitive trials, the hybrid mice performed worse than the AD model mice, who themselves performed worse than wildtype rodents. The result demonstrates that “[l]oss of memory is faster in this Alzheimer mouse model if the mice don’t have irisin,” Wrann writes in an email.

If a lack of irisin worsens memory loss in an AD model, could a boost of irisin improve cognitive function? The authors set out to answer this question with a gene therapy approach. Using a viral vector, the researchers boosted irisin production in the livers of their AD model mice, which translated into increased levels of the hormone in the mice’s blood and also in their brains. As the viral vector only increased irisin mRNA in the liver, the authors concluded that peripherally produced irisin was able to cross the blood-brain barrier.

This additional irisin seemed to improve the AD model mice’s cognitive function, even after amyloid plaques had formed in their brains: at 10 months of age, the irisin-treated animals performed significantly better in spatial learning and memory tasks than untreated ones, a conclusion that was supported by results from a different AD mouse model.

The data presented in the paper “convincingly show that peripherally administered irisin at pharmacological doses has really beneficial effects on cognition,” Maak writes in an email to The Scientist. He adds that the relevance of exercise in this context is not clear. “Irisin may have therapeutic potential at high concentrations. . . . I doubt whether pharmacological concentrations may be reached by exercise.”

How irisin, and especially peripherally delivered irisin, acts on the brain is not yet settled. When Wrann and coauthors examined morphology and gene expression in the mice’s brains, they observed that irisin-treated mice had fewer activated astrocytes and microglia, types of glial cells that play roles in the immune system in the brain, among other functions. “These different pieces of evidence support that irisin has an effect directly on astrocytes and possibly microglia,” says Wrann.

Meanwhile, in the irisin-deficient mice, the authors saw reduced dendritic spine density and smaller dendritic spine heads on adult-born hippocampal neurons, indicating that the neurons were developing abnormally. Whether the effect of irisin on glia influences adult hippocampal neurons is “an interesting, exciting question which we are going to work on right now,” she adds.

“I think [this study] opens this new field,” Sergio Ferreira, who specializes in biochemistry, biophysics and neurobiology at the Institute of Medical Biochemistry at the Federal University of Rio de Janeiro and was not involved in this study, tells The Scientist. “It’s very nice that [the authors] find that irisin appears to act by modulating or cooling down these glial cells and preventing the exacerbation of inflammatory responses, which may actually be damaging to the brain.” Ferreira published a 2019 paper reporting that irisin is important for memory in mice and that the hormone is reduced in AD mouse models, findings that were replicated in the new study, adding that the “glial avenue” of the work is “entirely new and very robust.”

See “Researchers Identify Irisin’s Receptor in Bone and Fat

One thing that stood out to Maak was that, despite significant changes in the brains of mice treated with irisin, the authors did not find any effects on fat tissue around the body, he says. The initial discovery of irisin—made in 2012 by a team led by Bruce Spiegelman, a coauthor of the current study—showed that irisin is elevated upon exercising, and acts on white adipose tissue to convert it into calorie-burning brown fat. In the new study, there was no effect on adipose tissue of any kind “in sharp contrast to previous results,” Maak says.

Wrann points to differences in the experimental models and setup as potential reasons why these discrepancies may have arisen, adding that the differing results “might tell something about the robustness of the effects on the brain versus the robustness on the effects on fat.”